MAJOR ARTICLE
Community Circulation Patterns of Oral Polio Vaccine Serotypes 1, 2, and 3 After Mexican National Immunization Weeks Stephanie B. Troy,1,a Leticia Ferreyra-Reyes,2,a ChunHong Huang,3 Clea Sarnquist,3 Sergio Canizales-Quintero,2 Christine Nelson,1 Renata Báez-Saldaña,2 Marisa Holubar,3 Elizabeth Ferreira-Guerrero,2 Lourdes García-García,2 and Yvonne A. Maldonado3 Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
1
Eastern Virginia Medical School, Norfolk, Virginia; 2Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México and 3Stanford University School of Medicine, Stanford, California
Background. With wild poliovirus nearing eradication, preventing circulating vaccine-derived poliovirus (cVDPV) by understanding oral polio vaccine (OPV) community circulation is increasingly important. Mexico, where OPV is given only during biannual national immunization weeks (NIWs) but where children receive inactivated polio vaccine (IPV) as part of their primary regimen, provides a natural setting to study OPV community circulation. Methods. In total, 216 children and household contacts in Veracruz, Mexico, were enrolled, and monthly stool samples and questionnaires collected for 1 year; 2501 stool samples underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3. Results. OPV was detected up to 7 months after an NIW, but not at 8 months. In total, 35% of samples collected from children vaccinated the prior month, but only 4% of other samples, contained OPV. Although each serotype was detected in similar proportions among OPV strains shed as a result of direct vaccination, 87% of OPV acquired through community spread was serotype 2 (P < .0001). Conclusions. Serotype 2 circulates longer and is transmitted more readily than serotypes 1 or 3 after NIWs in a Mexican community primarily vaccinated with IPV. This may be part of the reason why most isolated cVDPV has been serotype 2. Keywords.
polio; oral polio vaccine; inactivated polio vaccine; VDPV; Mexico.
Global wild poliovirus eradication may soon be achieved. Since 1988, when the World Health Organization proposed a plan to eradicate poliomyelitis, the number of reported annual global cases has dropped
Received 28 October 2013; accepted 11 December 2013; electronically published 23 December 2013. a These two authors contributed equally to this work. Meetings: Some of the data in this article were presented at the 50th annual meeting of the Infectious Diseases Society of America in San Diego, CA, in October, 2012 ( poster 247: Oral Polio Vaccine Shedding among Mexican Children after National Immunization Weeks) and at the 51st annual meeting of the Infectious Diseases Society of America in San Francisco, California, in October 2013 ( presentation 641: Differential Circulation Patterns of Oral Polio Vaccine Serotypes 1, 2, and 3 after Mexican National Immunization Weeks). Correspondence: Stephanie B. Troy, MD, Eastern Virginia Medical School, 825 Fairfax Ave, Ste 572, Norfolk, VA ([email protected]). The Journal of Infectious Diseases 2014;209:1693–9 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit831
from 350 000 to 223 in 2012 [1]. Only 3 countries remain endemic with uninterrupted transmission, and wild poliovirus serotype 2 has been eradicated for over a decade. The primary tool in the global eradication campaign has been oral polio vaccine (OPV), an inexpensive live attenuated vaccine that is easy to administer and promotes community immunity by spread from vaccinated children to community contacts through the fecal-oral route. However, despite its efficacy, OPV carries risks that will complicate the eradication effort. OPV consists of RNA viruses that can mutate during replication into forms capable of causing paralytic disease. Because about one out of 500 000 vaccinees develop vaccine-associated paralytic poliomyelitis (VAPP) from their first OPV dose, the United States has only used the more expensive inactivated polio vaccine (IPV), a killed virus vaccine that cannot cause poliomyelitis, since 2000 [2, 3]. Of more concern, with OPV Circulation Patterns in Mexico
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JID 2014:209 (1 June)
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1693
MATERIALS AND METHODS Study Design and Population
This was a prospective, longitudinal, observational study in 2 urban municipalities (Orizaba and Rio Blanco) and 2 rural municipalities (Rafael Delgado and Tlilapan) in Veracruz, Mexico, with a total population of 183 855 inhabitants. Of these, 14 573 (7.9%) were 5 years old or younger at the time of the study [8]. IPV, as a component of a pentavalent vaccine, has been given to children in Mexico at 2, 4, 6, and 18 months as part of the routine childhood immunization schedule since August of 2007. In addition, children 5 years old or younger who have received at least 2 doses of IPV are offered trivalent OPV during biannual national immunization weeks. Around the study period, there was 1 NIW 3 months before study enrollment (29 May to 4 June 2010), 1 NIW about 6 months after enrollment (15 to 19 February 2011), and 1 NIW about 9 months after enrollment (28 May to 3 June 2011). The study protocol was approved by the Ethics, Biosafety, and Research Committees of the Mexican National Institute of Public Health, by the Public Health Center of Orizaba, Veracruz, Mexico, by the Stanford University Institutional Review Board, and by the Eastern Virginia Medical School (EVMS) Institutional Review Board. 1694
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JID 2014:209 (1 June)
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Troy et al
For this observational study, 72 children from distinct households plus 2 household contacts per child, evenly distributed between the 4 municipalities, were enrolled between 25 August and 22 September 2010. Inclusion criteria for the enrolled children included age ≤30 months and having received or planning on receiving IPV as their primary polio vaccination regimen. Exclusion criteria for the enrolled children included international travel in the last 8 months, a household contact already enrolled in the study, an unknown vaccination history, or no household contacts willing to provide monthly stool samples. Household contacts could be any age and have any vaccination history but had to reside in the same household as the enrolled child; each household was allowed to choose which 2 household contacts would participate. The study was advertised at local health clinics, and families who expressed an interest in participating were referred to the study team. The first 18 children from each municipality who were referred to the study team and who fit the inclusion and exclusion criteria were enrolled in the study. After written informed consent was obtained from the parents and the household contacts (or the parents of the household contacts if children), participation included monthly study visits over the 12-month study period. At each visit, stool was collected from the enrolled child and the 2 household contacts, and questionnaires were completed that included details on health, vaccinations, travel, and demographics. Vaccination history for children was confirmed by checking immunization cards; immunization cards were not usually available for adult household contacts, although, per Mexican vaccination policy, none of them should have been vaccinated against polio since they were young children. Of note, given the timing of the national immunization weeks, monthly stool collections corresponded to 3, 4, 5, 6, 7, and 8 months after the May 2010 NIW, 0.5, 1.5, and 2.5 months after the February 2011 NIW, and 0.5, 1.5, and 2.5 months after the May 2011 NIW. Sewage was also collected from 4 arroyos (creeks) draining sewage from each of the 4 municipalities at monthly intervals; the analysis of the sewage has already been published elsewhere [9]. Stool Sample Analysis
On the day of collection, stool samples were kept in a cooler until brought to the lab, aliquoted into cryovials, and placed in a −80°C freezer. Samples were stored at −80°C except when shipped on dry ice to Dr Maldonado’s laboratory at Stanford, and when a portion of the samples were later shipped on dry ice to Dr Troy’s laboratory at EVMS. At Stanford and EVMS, stool underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to look for vaccine poliovirus serotypes-1, 2, and 3 and their revertant forms according to previously published methods with the following exception [10]. At EVMS, a 96 well ABI PRISM 7700 Real Time PCR Instrument was used (Applied Biosystems, Foster City, CA), with a threshold
Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
prolonged replication of typically more than one year, the viruses in OPV can mutate into vaccine-derived polioviruses (VDPV), which are 1%–15% divergent from parent OPV strains (0.6%–15% for serotype 2) [4]. VDPV can develop after persistent OPV virus replication in the intestinal tracts of individuals with primary humoral immunodeficiencies (iVDPV; 65 cases identified to date) or from continued person-to-person circulation in undervaccinated communities (cVDPV) [4]. From 2000 until September 2013, 23 separate cVDPV outbreaks in 20 different countries have been identified [5]. The one study, conducted in Nigeria, which compared outbreaks of cVDPV and wild poliovirus, suggests that cVDPV outbreaks have an attack rate and disease severity similar to outbreaks from wild poliovirus [6]. Because of the risks of poliomyelitis due to OPV, one of the components of the new “Polio Eradication and Endgame Strategic Plan 2013–2018” includes initiating at least 1 dose of IPV for children in countries that currently only use OPV and then phasing out OPV, starting by transitioning from trivalent OPV to bivalent OPV, which contains only serotypes 1 and 3 [7]. Unknown factors that could affect this new plan include the duration and pattern of OPV-derived virus circulation in a community vaccinated with IPV. To help fill those knowledge gaps, we conducted a study looking at the circulation patterns of OPV and OPV-derived strains in Mexico, a country that introduced IPV into its regular childhood vaccination schedule in 2007 but continues to give OPV twice a year during national immunization weeks (NIW).
of 0.099 ΔRn for detecting fluorescence. In total, 53 samples were analyzed in duplicate at both Stanford and EVMS to confirm consistency of results between the 2 laboratories.
Table 1.
Categorization of Method of OPV Acquisition
N Mean age at enrollment (range) in years
Statistical Analysis
Categorical data were compared using a 2-tailed Fisher exact test. A P value of ≤ .05 was considered statistically significant. Analysis was performed in SAS 9.1 (Cary, NC).
Age distribution at Enrollment: 40 y old Gender: % female
0 (0%)
21 (15%)
0 (0%) 37 (51%)
13 (9%) 99 (69%)
Received OPV in May 2010 NIW
35 (49%)
4 (3%)
Received OPV in February 2011 NIWa
47 (68%)
6 (4%)
Received OPV in May 2011 NIWa Received all recommended IPV doses for age at enrollment
46 (67%)
7 (5%)
53 (74%)
NA
Mean prior IPV doses at enrollment International travel in the last 8 mo
2.9
NA
0 (0%)
0 (0%)
Known Immunosuppression Rural (vs urban) residence
0 (0%) 36 (50%)
0 (0%) 72 (50%)
Residence with dirt floor
8 (11%)
16 (11%)
Residence without indoor plumbing
34 (47%)
68 (47%)
Mean no. of children in household Mean no. of children in household 85% of cVDPV isolated from global outbreaks to date have been serotype 2 [5]. The increased fitness of serotype 2 compared to serotypes 1 and 3 has been known since OPV was first developed and is the reason behind the subsequent formulation changes in trivalent OPV [14]. Serotype 2 was reported to be more transmissible compared to the other serotypes in studies from Russia and the United States conducted between 1957 and 1960, which examined shedding in household contacts of recipients of older formulations of trivalent OPV [15–17]. Very early studies also showed that when the 3 serotypes were given together in equal amounts, serotype 2 was shed more than the other serotypes, and seroconversion was higher for serotype 2 than the other serotypes among vaccinees [18]. As a consequence, the formulation of trivalent OPV was “balanced” so that the ratio of serotypes 1, 2, and 3 was 10:1:3 in around 1963, and the minimum concentration of serotype 3 was further increased by recommendation of the World Health Organization Global Advisory Group in the early 1990s. There have been limited studies on community circulation of OPV in the past several decades, especially since the introduction of newer vaccine formulations and the inclusion of IPV-vaccinated populations in developing settings. An American OPV Circulation Patterns in Mexico
•
JID 2014:209 (1 June)
•
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Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
Figure 3.
Table 2.
Type and Number of Serotypes Shed by Subjects Who Acquired OPV Virus Through Direct Vaccination vs Community Spread Community Acquisition (n = 78)
Direct Vaccination (n = 64) Serotype shed
n
%
95% CIa
Any Type 1
25
39.1%
28.0%–51.3%
4
Any Type 2 Any Type 3
35 38
54.7% 59.4%
42.6%–66.3% 47.1%–70.6%
68 10
n
95% C.I.a
P Value*
5.1%
2.1%–11.2%
Community Circulation Patterns of Oral Polio Vaccine Serotypes 1, 2, and 3 After Mexican National Immunization Weeks Stephanie B. Troy,1,a Leticia Ferreyra-Reyes,2,a ChunHong Huang,3 Clea Sarnquist,3 Sergio Canizales-Quintero,2 Christine Nelson,1 Renata Báez-Saldaña,2 Marisa Holubar,3 Elizabeth Ferreira-Guerrero,2 Lourdes García-García,2 and Yvonne A. Maldonado3 Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
1
Eastern Virginia Medical School, Norfolk, Virginia; 2Instituto Nacional de Salud Pública, Cuernavaca, Morelos, México and 3Stanford University School of Medicine, Stanford, California
Background. With wild poliovirus nearing eradication, preventing circulating vaccine-derived poliovirus (cVDPV) by understanding oral polio vaccine (OPV) community circulation is increasingly important. Mexico, where OPV is given only during biannual national immunization weeks (NIWs) but where children receive inactivated polio vaccine (IPV) as part of their primary regimen, provides a natural setting to study OPV community circulation. Methods. In total, 216 children and household contacts in Veracruz, Mexico, were enrolled, and monthly stool samples and questionnaires collected for 1 year; 2501 stool samples underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3. Results. OPV was detected up to 7 months after an NIW, but not at 8 months. In total, 35% of samples collected from children vaccinated the prior month, but only 4% of other samples, contained OPV. Although each serotype was detected in similar proportions among OPV strains shed as a result of direct vaccination, 87% of OPV acquired through community spread was serotype 2 (P < .0001). Conclusions. Serotype 2 circulates longer and is transmitted more readily than serotypes 1 or 3 after NIWs in a Mexican community primarily vaccinated with IPV. This may be part of the reason why most isolated cVDPV has been serotype 2. Keywords.
polio; oral polio vaccine; inactivated polio vaccine; VDPV; Mexico.
Global wild poliovirus eradication may soon be achieved. Since 1988, when the World Health Organization proposed a plan to eradicate poliomyelitis, the number of reported annual global cases has dropped
Received 28 October 2013; accepted 11 December 2013; electronically published 23 December 2013. a These two authors contributed equally to this work. Meetings: Some of the data in this article were presented at the 50th annual meeting of the Infectious Diseases Society of America in San Diego, CA, in October, 2012 ( poster 247: Oral Polio Vaccine Shedding among Mexican Children after National Immunization Weeks) and at the 51st annual meeting of the Infectious Diseases Society of America in San Francisco, California, in October 2013 ( presentation 641: Differential Circulation Patterns of Oral Polio Vaccine Serotypes 1, 2, and 3 after Mexican National Immunization Weeks). Correspondence: Stephanie B. Troy, MD, Eastern Virginia Medical School, 825 Fairfax Ave, Ste 572, Norfolk, VA ([email protected]). The Journal of Infectious Diseases 2014;209:1693–9 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit831
from 350 000 to 223 in 2012 [1]. Only 3 countries remain endemic with uninterrupted transmission, and wild poliovirus serotype 2 has been eradicated for over a decade. The primary tool in the global eradication campaign has been oral polio vaccine (OPV), an inexpensive live attenuated vaccine that is easy to administer and promotes community immunity by spread from vaccinated children to community contacts through the fecal-oral route. However, despite its efficacy, OPV carries risks that will complicate the eradication effort. OPV consists of RNA viruses that can mutate during replication into forms capable of causing paralytic disease. Because about one out of 500 000 vaccinees develop vaccine-associated paralytic poliomyelitis (VAPP) from their first OPV dose, the United States has only used the more expensive inactivated polio vaccine (IPV), a killed virus vaccine that cannot cause poliomyelitis, since 2000 [2, 3]. Of more concern, with OPV Circulation Patterns in Mexico
•
JID 2014:209 (1 June)
•
1693
MATERIALS AND METHODS Study Design and Population
This was a prospective, longitudinal, observational study in 2 urban municipalities (Orizaba and Rio Blanco) and 2 rural municipalities (Rafael Delgado and Tlilapan) in Veracruz, Mexico, with a total population of 183 855 inhabitants. Of these, 14 573 (7.9%) were 5 years old or younger at the time of the study [8]. IPV, as a component of a pentavalent vaccine, has been given to children in Mexico at 2, 4, 6, and 18 months as part of the routine childhood immunization schedule since August of 2007. In addition, children 5 years old or younger who have received at least 2 doses of IPV are offered trivalent OPV during biannual national immunization weeks. Around the study period, there was 1 NIW 3 months before study enrollment (29 May to 4 June 2010), 1 NIW about 6 months after enrollment (15 to 19 February 2011), and 1 NIW about 9 months after enrollment (28 May to 3 June 2011). The study protocol was approved by the Ethics, Biosafety, and Research Committees of the Mexican National Institute of Public Health, by the Public Health Center of Orizaba, Veracruz, Mexico, by the Stanford University Institutional Review Board, and by the Eastern Virginia Medical School (EVMS) Institutional Review Board. 1694
•
JID 2014:209 (1 June)
•
Troy et al
For this observational study, 72 children from distinct households plus 2 household contacts per child, evenly distributed between the 4 municipalities, were enrolled between 25 August and 22 September 2010. Inclusion criteria for the enrolled children included age ≤30 months and having received or planning on receiving IPV as their primary polio vaccination regimen. Exclusion criteria for the enrolled children included international travel in the last 8 months, a household contact already enrolled in the study, an unknown vaccination history, or no household contacts willing to provide monthly stool samples. Household contacts could be any age and have any vaccination history but had to reside in the same household as the enrolled child; each household was allowed to choose which 2 household contacts would participate. The study was advertised at local health clinics, and families who expressed an interest in participating were referred to the study team. The first 18 children from each municipality who were referred to the study team and who fit the inclusion and exclusion criteria were enrolled in the study. After written informed consent was obtained from the parents and the household contacts (or the parents of the household contacts if children), participation included monthly study visits over the 12-month study period. At each visit, stool was collected from the enrolled child and the 2 household contacts, and questionnaires were completed that included details on health, vaccinations, travel, and demographics. Vaccination history for children was confirmed by checking immunization cards; immunization cards were not usually available for adult household contacts, although, per Mexican vaccination policy, none of them should have been vaccinated against polio since they were young children. Of note, given the timing of the national immunization weeks, monthly stool collections corresponded to 3, 4, 5, 6, 7, and 8 months after the May 2010 NIW, 0.5, 1.5, and 2.5 months after the February 2011 NIW, and 0.5, 1.5, and 2.5 months after the May 2011 NIW. Sewage was also collected from 4 arroyos (creeks) draining sewage from each of the 4 municipalities at monthly intervals; the analysis of the sewage has already been published elsewhere [9]. Stool Sample Analysis
On the day of collection, stool samples were kept in a cooler until brought to the lab, aliquoted into cryovials, and placed in a −80°C freezer. Samples were stored at −80°C except when shipped on dry ice to Dr Maldonado’s laboratory at Stanford, and when a portion of the samples were later shipped on dry ice to Dr Troy’s laboratory at EVMS. At Stanford and EVMS, stool underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to look for vaccine poliovirus serotypes-1, 2, and 3 and their revertant forms according to previously published methods with the following exception [10]. At EVMS, a 96 well ABI PRISM 7700 Real Time PCR Instrument was used (Applied Biosystems, Foster City, CA), with a threshold
Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
prolonged replication of typically more than one year, the viruses in OPV can mutate into vaccine-derived polioviruses (VDPV), which are 1%–15% divergent from parent OPV strains (0.6%–15% for serotype 2) [4]. VDPV can develop after persistent OPV virus replication in the intestinal tracts of individuals with primary humoral immunodeficiencies (iVDPV; 65 cases identified to date) or from continued person-to-person circulation in undervaccinated communities (cVDPV) [4]. From 2000 until September 2013, 23 separate cVDPV outbreaks in 20 different countries have been identified [5]. The one study, conducted in Nigeria, which compared outbreaks of cVDPV and wild poliovirus, suggests that cVDPV outbreaks have an attack rate and disease severity similar to outbreaks from wild poliovirus [6]. Because of the risks of poliomyelitis due to OPV, one of the components of the new “Polio Eradication and Endgame Strategic Plan 2013–2018” includes initiating at least 1 dose of IPV for children in countries that currently only use OPV and then phasing out OPV, starting by transitioning from trivalent OPV to bivalent OPV, which contains only serotypes 1 and 3 [7]. Unknown factors that could affect this new plan include the duration and pattern of OPV-derived virus circulation in a community vaccinated with IPV. To help fill those knowledge gaps, we conducted a study looking at the circulation patterns of OPV and OPV-derived strains in Mexico, a country that introduced IPV into its regular childhood vaccination schedule in 2007 but continues to give OPV twice a year during national immunization weeks (NIW).
of 0.099 ΔRn for detecting fluorescence. In total, 53 samples were analyzed in duplicate at both Stanford and EVMS to confirm consistency of results between the 2 laboratories.
Table 1.
Categorization of Method of OPV Acquisition
N Mean age at enrollment (range) in years
Statistical Analysis
Categorical data were compared using a 2-tailed Fisher exact test. A P value of ≤ .05 was considered statistically significant. Analysis was performed in SAS 9.1 (Cary, NC).
Age distribution at Enrollment: 40 y old Gender: % female
0 (0%)
21 (15%)
0 (0%) 37 (51%)
13 (9%) 99 (69%)
Received OPV in May 2010 NIW
35 (49%)
4 (3%)
Received OPV in February 2011 NIWa
47 (68%)
6 (4%)
Received OPV in May 2011 NIWa Received all recommended IPV doses for age at enrollment
46 (67%)
7 (5%)
53 (74%)
NA
Mean prior IPV doses at enrollment International travel in the last 8 mo
2.9
NA
0 (0%)
0 (0%)
Known Immunosuppression Rural (vs urban) residence
0 (0%) 36 (50%)
0 (0%) 72 (50%)
Residence with dirt floor
8 (11%)
16 (11%)
Residence without indoor plumbing
34 (47%)
68 (47%)
Mean no. of children in household Mean no. of children in household 85% of cVDPV isolated from global outbreaks to date have been serotype 2 [5]. The increased fitness of serotype 2 compared to serotypes 1 and 3 has been known since OPV was first developed and is the reason behind the subsequent formulation changes in trivalent OPV [14]. Serotype 2 was reported to be more transmissible compared to the other serotypes in studies from Russia and the United States conducted between 1957 and 1960, which examined shedding in household contacts of recipients of older formulations of trivalent OPV [15–17]. Very early studies also showed that when the 3 serotypes were given together in equal amounts, serotype 2 was shed more than the other serotypes, and seroconversion was higher for serotype 2 than the other serotypes among vaccinees [18]. As a consequence, the formulation of trivalent OPV was “balanced” so that the ratio of serotypes 1, 2, and 3 was 10:1:3 in around 1963, and the minimum concentration of serotype 3 was further increased by recommendation of the World Health Organization Global Advisory Group in the early 1990s. There have been limited studies on community circulation of OPV in the past several decades, especially since the introduction of newer vaccine formulations and the inclusion of IPV-vaccinated populations in developing settings. An American OPV Circulation Patterns in Mexico
•
JID 2014:209 (1 June)
•
1697
Downloaded from http://jid.oxfordjournals.org/ at Central Michigan University on September 13, 2015
Figure 3.
Table 2.
Type and Number of Serotypes Shed by Subjects Who Acquired OPV Virus Through Direct Vaccination vs Community Spread Community Acquisition (n = 78)
Direct Vaccination (n = 64) Serotype shed
n
%
95% CIa
Any Type 1
25
39.1%
28.0%–51.3%
4
Any Type 2 Any Type 3
35 38
54.7% 59.4%
42.6%–66.3% 47.1%–70.6%
68 10
n
95% C.I.a
P Value*
5.1%
2.1%–11.2%
